tbuckley/cabot-search huggingface dataset:
Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions
Authors: Zsolt Megyesfalvi, Carl M. Gay, Helmut Popper, Robert Pirker, Gyula Ostoros, Simon Heeke, Christian Lang, Konrad Hoetzenecker, Anna Schwendenwein, Kristiina Boettiger, Paul A. Bunn, Ferenc Renyi‐Vamos, Karin Schelch, Helmut Prosch, Lauren A. Byers, Fred R. Hirsch, Balazs Dome
Journal: CA A Cancer Journal for Clinicians (2023)

Abstract Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1 , and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative‐intent lung resection, and these individuals require adjuvant platinum‐etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum‐etoposide chemotherapy. Patients with metastatic (extensive‐stage) disease are treated with a combination of platinum‐etoposide chemotherapy plus immunotherapy with an anti‐programmed death‐ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum‐based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
Isoprostane, an “Intermediate Phenotype” for Oxidative Stress
Authors: Fangwen Rao, Kuixing Zhang, Srikrishna Khandrika, Manjula Mahata, Maple M. Fung, Michael G. Ziegler, Brinda K. Rana, Daniel T. O'Connor
Journal: Journal of the American College of Cardiology (2010)
ESMO-Magnitude of Clinical Benefit Scale for haematological malignancies (ESMO-MCBS:H) version 1.0
Authors: B. Kiesewetter, U. Dafni, E.G.E. de Vries, J. Barriuso, G. Curigliano, V. González-Calle, M. Galotti, B. Gyawali, B.J.P. Huntly, U. Jäger, N.J. Latino, L. Malcovati, S.F. Oosting, G. Ossenkoppele, M. Piccart, M. Raderer, L. Scarfò, D. Trapani, C.C. Zielinski, R. Wester, P. Zygoura, E. Macintyre, N.I. Cherny
Journal: Annals of Oncology (2023)
Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock
Authors: Maj-Brit Nørregaard Kjær, Tine Sylvest Meyhoff, Praleene Sivapalan, Anders Granholm, Peter Buhl Hjortrup, Martin Bruun Madsen, Morten Hylander Møller, Ingrid Egerod, Jørn Wetterslev, Theis Lange, Maria Cronhjort, Jon Henrik Laake, Stephan M. Jakob, Marek Nalos, Marlies Ostermann, Doug Gould, Maurizio Cecconi, Manu L. N. G. Malbrain, Christian Ahlstedt, Louise Bendix Kiel, Morten H. Bestle, Lars Nebrich, Thomas Hildebrandt, Lene Russell, Marianne Vang, Michael Lindhart Rasmussen, Christoffer Sølling, Anne Craveiro Brøchner, Mette Krag, Carmen Pfortmueller, Miroslav Kriz, Martin Siegemund, Giovanni Albano, Søren Rosborg Aagaard, Helle Bundgaard, Vera Crone, Sine Wichmann, Bror Johnstad, Yvonne Karin Martin, Philipp Seidel, Johan Mårtensson, Jacob Hollenberg, Mats Wistrand, Abele Donati, Enrico Barbara, Thomas Karvunidis, Alexa Hollinger, Andrea Carsetti, Nuttha Lumlertgul, Eva Joelsson-Alm, Nikolas Lambiris, Tayyba Naz Aslam, Fredrik Femtehjell Friberg, Gitte Kingo Vesterlund, Camilla Bekker Mortensen, Stine Rom Vestergaard, Sidsel Fjordbak Caspersen, Diana Bertelsen Jensen, Morten Borup, Bodil Steen Rasmussen, Anders Perner
Journal: Intensive Care Medicine (2023)

To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial.
Tubulointerstitial nephritis antigen-like 1 is a novel matricellular protein that promotes gastric bacterial colonization and gastritis in the setting of Helicobacter pylori infection
Authors: Yongsheng Teng, Rui Xie, Jingyu Xu, Pan Wang, Wanyan Chen, Zhiguo Shan, Zongbao Yan, Fangyuan Mao, Ping Cheng, Liusheng Peng, Jinyu Zhang, Wenqing Tian, Shiming Yang, Yongliang Zhao, Weisan Chen, Quanming Zou, Yuan Zhuang
Journal: Cellular and Molecular Immunology (2023)
Emergence of resistance-associated variants during sofosbuvir treatment in chronically infected hepatitis E patients
Authors: André Gömer, Mara Klöhn, Michelle Jagst, Maximilian K. Nocke, Sven Pischke, Thomas Horvatits, Julian Schulze zur Wiesch, Tobias Müller, Svenja Hardtke, Markus Cornberg, Heiner Wedemeyer, Patrick Behrendt, Eike Steinmann, Daniel Todt
Journal: Hepatology (2023)

Background and Aims: Chronic HEV infections remain a serious problem in immunocompromised patients, as specifically approved antiviral drugs are unavailable. In 2020, a 24-week multicenter phase II pilot trial was carried out, evaluating the nucleotide analog sofosbuvir by treating nine chronically HEV-infected patients with sofosbuvir (Trial Number NCT03282474). During the study, antiviral therapy reduced virus RNA levels initially but did not lead to a sustained virologic response. Here, we characterize the changes in HEV intrahost populations during sofosbuvir treatment to identify the emergence of treatment-associated variants. Approach and Results: We performed high-throughput sequencing on RNA-dependent RNA polymerase sequences to characterize viral population dynamics in study participants. Subsequently, we used an HEV-based reporter replicon system to investigate sofosbuvir sensitivity in high-frequency variants. Most patients had heterogenous HEV populations, suggesting high adaptability to treatment-related selection pressures. We identified numerous amino acid alterations emerging during treatment and found that the EC 50 of patient-derived replicon constructs was up to ~12-fold higher than the wild-type control, suggesting that variants associated with lower drug sensitivity were selected during sofosbuvir treatment. In particular, a single amino acid substitution (A1343V) in the finger domain of ORF1 could reduce susceptibility to sofosbuvir significantly in 8 of 9 patients. Conclusions: In conclusion, viral population dynamics played a critical role during antiviral treatment. High population diversity during sofosbuvir treatment led to the selection of variants (especially A1343V) with lower sensitivity to the drug, uncovering a novel mechanism of resistance-associated variants during sofosbuvir treatment.
Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis
Authors: Nneoma Adaku, Benjamin N. Ostendorf, Wenbin Mei, Sohail F. Tavazoie
Journal: Cancer Research (2023)

Abstract The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of melanoma progression. The APOE germline genotype predicts human melanoma outcomes, with APOE4 and APOE2 allele carriers exhibiting prolonged and reduced survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing antitumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2&amp;gt;APOE3&amp;gt;APOE4 manner. The low-density lipoprotein receptor-related protein 1 (LRP1) receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer's disease. Significance: APOE germline variants impact melanoma progression through disparate mechanisms, such as the protein synthesis–promoting function of the APOE2 variant, indicating that germline genetic variants are causal contributors to metastatic outcomes.
First‐Aid Hydrogel Wound Dressing with Reliable Hemostatic and Antibacterial Capability for Traumatic Injuries
Authors: Junyao Cheng, Hufei Wang, Jianpeng Gao, Xiao Liu, Ming Li, Decheng Wu, Jianheng Liu, Xing Wang, Zheng Wang, Peifu Tang
Journal: Advanced Healthcare Materials (2023)

First-aid for severe traumatic injuries in the battlefield or pre-hospital environment, especially for skin defects or visceral rupture, remains a substantial medical challenge even in the context of the rapidly evolving modern medical technology. Hydrogel-based biomaterials are highly anticipated for excellent biocompatibility and bio-functional designability. Yet, inadequate mechanical and bio-adhesion properties limit their clinical application. To address these challenges, a kind of multifunctional hydrogel wound dressing is developed with the collective multi-crosslinking advantages of dynamic covalent bonds, metal-catechol chelation, and hydrogen bonds. The mussel-inspired design and zinc oxide-enhanced cohesion strategy collaboratively reinforce the hydrogel's bio-adhesion in bloody or humoral environments. The pH-sensitive coordinate Zn2+ -catechol bond and dynamic Schiff base with reversible breakage and reformation equip the hydrogel dressing with excellent self-healing and on-demand removal properties. In vivo evaluation in a rat ventricular perforation model and Methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness skin defect model reveal excellent hemostatic, antibacterial and pro-healing effectiveness of the hydrogel dressing, demonstrating its great potential in dealing with severe bleeding and infected full-thickness skin wounds.
Abstract 15033: Chronic Thromboembolic Pulmonary Hypertension Patients Have Reduced Bi-Ventricular Myocardial Perfusion Reserve, Which Improves Following Pulmonary Thromboendarterectomy
Authors: Lexiaozi Fan, Daniel C Lee, Brandon C Benefield, S. Christopher Malaisrie, Michael Cuttica, Li-Yueh Hsu, Bradley D Allen, Daniel R Schimmel, Ryan Avery, Benjamin Freed, Daniel Kim
Journal: Circulation (2022)

Introduction: This study seeks to determine whether bi-ventricular myocardial perfusion reserve (MPR) is reduced in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared to a control group using quantitative myocardial perfusion MRI. Methods: We prospectively enrolled 4 CTEPH patients (55±14 years, 4 males) and performed stress-rest (10 min apart) protocol using our 5-fold accelerated radial perfusion sequence. In one patient, we repeated stress-rest perfusion acquisition following pulmonary thromboendarterectomy (PTE). As a control group, we retrospectively identified 8 subjects (49±12 years, 5 males) with no evidence of vascular late gadolinium enhancement or perfusion defects who underwent a similar stress-rest protocol. The pixel-wise stress-rest myocardial blood flow (MBF) maps and MPR were quantified for both the left ventricular (LV) and right ventricular (RV) free walls. Two sample t-test was used to compare between the CTEPH and control groups. Results: Figure 1a shows representative stress and rest MBF maps and the corresponding MPR values comparing a CTEPH patient and a control subject. Summarizing the results of all patients (Figure 1b), compared to the control group, the CTEPH group had significantly (p &lt; 0.05) lower stress LV MBF (1.56 ± 0.34 vs. 2.66 ± 0.50 ml/g/min), RV MBF (1.48 ± 0.19 vs. 2.56 ± 0.53 ml/g/min), LV MPR (1.65 ± 0.43 vs. 2.32 ± 0.50), and RV MPR (1.59±0.46 vs. 2.50 ± 0.53), but non-significant difference (p &gt; 0.05) in resting LV MBF (0.96 ± 0.12 vs. 1.21 ± 0.43 ml/g/min) and RV MBF (0.96 ± 0.14 vs. 1.07 ± 0.36 ml/g/min). In one patient, PTE improved RV MPR from 1.43 to 2.49 as well as LV MPR from 1.24 to 2.36. Conclusions: This study suggests that both RV and LV MPR are reduced in CTEPH patients compared with controls and that PTE may improve RV as well as LV MPR in CTEPH patients. Future studies include additional enrollment of CTEPH patients, determining the diagnostic and prognostic role of RV and LV MPR in the context of PTE.
Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis
Authors: Hiroshi Nango, Komugi Tsuruta, Hiroko Miyagishi, Yuri Aono, Tadashi Saigusa, Yasuhiro Kosuge
Journal: Translational Neurodegeneration (2023)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E2 (PGE2) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE2, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE2-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.
Proteomics of immune cells from liver tumors reveals immunotherapy targets
Authors: Fernando P. Canale, Julia Neumann, Janusz von Renesse, Elisabetta Loggi, Matteo Pecoraro, Ian Vogel, Giada Zoppi, Gaia Antonini, Tobias Wolf, Wenjie Jin, Xiaoqin Zheng, Giuliano La Barba, Emrullah Birgin, Marianne Forkel, Tobias Nilsson, Romina Marone, Henrik Mueller, Nadege Pelletier, Lukas T. Jeker, Gianluca Civenni, Christoph Schlapbach, Carlo V. Catapano, Lena Seifert, Adrian M. Seifert, Silke Gillessen, Sara De Dosso, Alessandra Cristaudi, Nuh N. Rahbari, Giorgio Ercolani, Roger Geiger
Journal: Cell Genomics (2023)

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.
A European‐Japanese study on peach allergy: <scp>IgE</scp> to Pru p 7 associates with severity
Authors: E. J. J. Kallen, A. Revers, M. Fernández‐Rivas, R. Asero, B. Ballmer‐Weber, L. Barreales, S. Belohlavkova, F. de Blay, M. Clausen, R. Dubakiene, M. Ebisawa, C. Fernández‐Perez, P. Fritsche, Y. Fukutomi, D. Gislason, K. Hoffmann‐Sommergruber, M. Jedrzejczak‐Czechowicz, A. C. Knulst, M. L. Kowalski, T. Kralimarkova, J. Lidholm, C. Metzler, E. N. C. Mills, N. G. Papadopoulos, T. A. Popov, A. Purohit, I. Reig, S. L. Seneviratne, A. Sinaniotis, M. Takei, S. A. Versteeg, A. E. Vassilopoulou, S. Vieths, P. M. J. Welsing, A. H. Zwinderman, T. M. Le, R. Van Ree
Journal: Allergy (2023)

Pru p 3 and Pru p 7 have been implicated as risk factors for severe peach allergy. This study aimed to establish sensitization patterns to five peach components across Europe and in Japan, to explore their relation to pollen and foods and to predict symptom severity.In twelve European (EuroPrevall project) and one Japanese outpatient clinic, a standardized clinical evaluation was conducted in 1231 patients who reported symptoms to peach and/or were sensitized to peach. Specific IgE against Pru p 1, 2, 3, 4 and 7 and against Cup s 7 was measured in 474 of them. Univariable and multivariable Lasso regression was applied to identify combinations of parameters predicting severity.Sensitization to Pru p 3 dominated in Southern Europe but was also quite common in Northern and Central Europe. Sensitization to Pru p 7 was low and variable in the European centers but very dominant in Japan. Severity could be predicted by a model combining age of onset of peach allergy, probable mugwort, Parietaria pollen and latex allergy, and sensitization to Japanese cedar pollen, Pru p 4 and Pru p 7 which resulted in an AUC of 0.73 (95% CI 0.73-0.74). Pru p 3 tended to be a risk factor in South Europe only.Pru p 7 was confirmed as a significant risk factor for severe peach allergy in Europe and Japan. Combining outcomes from clinical and demographic background with serology resulted in a model that could better predict severity than CRD alone.
Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice
Authors: Sounak Ghosh Roy, Zhigui Li, Zi Guo, Kelly Tran Long, Sonja Rehrl, Xin Tian, Ke Dong, Whitney Besse
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Heterozygous DNAJB11 mutation carriers manifest with small cystic kidneys and renal failure in adulthood. Recessive cases with prenatal cystic kidney dysplasia were recently described. Our in vitro and mouse model studies investigate the proposed disease mechanism as an overlap of autosomal-dominant polycystic kidney disease and autosomal-dominant tubulointerstitial kidney disease pathogenesis. We find that DNAJB11 loss impairs cleavage and maturation of the autosomal-dominant polycystic kidney disease protein polycystin-1 (PC1) and results in dosage-dependent cyst formation in mice. We find that Dnajb11 loss does not activate the unfolded protein response, drawing a fundamental contrast with the pathogenesis of autosomal-dominant tubulointerstitial kidney disease. We instead propose that fibrosis in DNAJB11 -kidney disease may represent an exaggerated response to polycystin-dependent cysts. Background Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo . DNAJB11 encodes an Hsp40 cochaperone in the endoplasmic reticulum: the site of maturation of the ADPKD polycystin-1 (PC1) protein and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases. Methods We used germline and conditional alleles to model Dnajb11 -kidney disease in mice. In complementary experiments, we generated two novel Dnajb11 −/− cell lines that allow assessment of PC1 C-terminal fragment and its ratio to the immature full-length protein. Results Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11 −/− mice are live-born at below the expected Mendelian ratio and die at a weaning age with cystic kidneys. Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mouse models show no evidence of UPR activation or cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis. Conclusions DNAJB11 -kidney disease is on the spectrum of ADPKD phenotypes with a PC1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.
L-Arabinose inhibits Shiga toxin type 2-converting bacteriophage induction in <i>Escherichia coli</i> O157:H7
Authors: Jie Hu, Yifan Wu, Xingjian Zhou, Luyuan Kang, Shiyi Zhang, Yisi Liu, Yu Pi, Xilong Li, Junjun Wang, Dandan Han
Journal: Gut Microbes (2023)

The pathogenicity of Escherichia coli (E. coli) O157:H7 is predominantly associated with Shiga toxin 2 (Stx2) that poses a huge threat to human and animal intestinal health. Production of Stx2 requires expression of stx2 gene, which is located in the genome of lambdoid Stx2 prophage. Growing evidence has implicated that many commonly consumed foods participate in the regulation of prophage induction. In this study, we aimed to explore whether specific dietary functional sugars could inhibit Stx2 prophage induction in E. coli O157:H7, thereby preventing Stx2 production and promoting intestinal health. We demonstrated that Stx2 prophage induction in E. coli O157:H7 was strongly inhibited by L-arabinose both in vitro and in a mouse model. Mechanistically, L-arabinose at doses of 9, 12, or 15 mM diminished RecA protein levels, a master mediator of the SOS response, contributing to reduced Stx2-converting phage induction. L-Arabinose inhibited quorum sensing and oxidative stress response, which are known as positive regulators of the SOS response and subsequent Stx2 phage production. Furthermore, L-arabinose impaired E. coli O157:H7 arginine transport and metabolism that were involved in producing Stx2 phage. Collectively, our results suggest that L-arabinose may be exploited as a novel Stx2 prophage induction inhibitor against E. coli O157:H7 infection.